The term "cyclosporin" as used herein refers to any member of a class of nonpolar polypeptides, as defined in the Merck Index, Twelfth Edition. One such cyclosporin is cyclosporin A, also known as "cyclosporine" and hereinafter referred to as "cyclosporine", known to be therapeutically active as an immunosuppressant.
Cyclosporins are hydrophobic and have low solubility in aqueous media. This makes it difficult to design pharmaceutical compositions (i.e. dosage forms) comprising cyclosporins which exhibit satisfactory absorption into systemic circulation after oral administration.
The cyclosporin can be dissolved in an organic solvent (e.g. ethanol or propylene glycol), but, if the solvent is water-miscible, when the composition is mixed with gastrointestinal fluid or other aqueous medium, the cyclosporin will precipitate.
Methods of overcoming this problem are known in the prior art. The most common approach is to dissolve the cyclosporin in a solvent system that comprises at least one lipophilic (hydrophobic) solvent and a surfactant, so that the composition disperses into an emulsion when mixed into gastrointestinal fluid or other aqueous medium.
Such compositions are called "emulsion preconcentrates".
U.S. Pat. No. 4,388,307 discloses such compositions. A commercial product that has been sold under the trademark Sandimmune (registered trademark) is made according to U.S. Pat. No. 4,388,307, and, more specifically, comprises cyclosporine dissolved in a solvent system comprising ethanol as hydrophilic solvent, a vegetable oil as lipophilic solvent, and a surfactant. The ethanol is required to dissolve the cyclosporine in the composition, as the vegetable oil has inadequate capacity to dissolve cyclosporins.
Sandimmune (registered trademark) is sold in the form of both an oral liquid, which is an emulsion preconcentrate intended to be diluted into an aqueous drink before ingestion, and a soft gelatin capsule containing the emulsion preconcentrate.
U.S. Pat. No. 5,342,625 discloses compositions that are superior in certain respects to the compositions taught in U.S. Pat. No. 4,388,307. The compositions of U.S. Pat. No. 5,342,625 again comprise, cyclosporine, a hydrophilic solvent, a lipophilic (i.e. hydrophobic) solvent and a surfactant. The hydrophilic solvent is either propylene glycol or an alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkanediol.
Compositions according to U.S. Pat. No. 5,342,625, when added to water, disperse into emulsions with droplet size of less than 2000 .ANG. which is smaller than those obtained with prior art compositions, thus leading to improved absorption.
Emulsions with droplet size of less than 2000 .ANG. are defined as "microemulsions". Compositions that, upon addition to water, disperse into microemulsions are called "microemulsion preconcentrates".
A composition made according to the disclosure of U.S. Pat. No. 5,342,625 is now marketed under the trademark Neoral (registered trademark). As is the case with Sandimmune (registered trademark), Neoral (registered trademark) is available as both an oral liquid and soft gelatin capsules.
For both the soft gelatin capsules and the oral liquid, Neoral (registered trademark) microemulsion preconcentrate comprises cyclosporine dissolved in ethanol and propylene glycol as hydrophilic solvents, corn oil glycerides as lipophilic solvent, and polyoxyl 40 hydrogenated castor oil as surfactant. It also contains dl-alpha-tocopherol at a level of about one percent by weight as antioxidant.
For both Sandimmune (registered trademark) and Neoral (registered trademark), the capsule formulations have certain undesirable features.
Specifically:
1. They both contain ethanol, which is volatile. This means that the capsules must be individually packaged in metal pouches to avoid evaporation of the ethanol.
2. The capsules are relatively large and difficult to swallow. This is because the formulations must contain substantial quantities of the hydrophilic and lipophilic solvents, which are needed to keep the cyclosporine and surfactant in solution. The total weight of contents of each capsule is about ten times the weight of the cyclosporine contained therein.
The prior art discloses some attempts to overcome these problems by use of formulations that contain the cyclosporin and surfactant, but no solvent.
Such compositions are solid in form and can be used to make tablets or as a fill for two-piece hard gelatin capsules.
Japanese No. 2536876 of Takada et al discloses powdery preparations comprising a cyclosporin dispersed in a solid, non-surfactant carrier together with a surfactant. All of the examples in this patent use as the surfactant polyoxyethylene hydrogenated castor oil, which is non-ionic. In the examples, the total weight of the compositions is from 5 to 151 times the weight of the cyclosporin, and it appears unlikely that any of the disclosed compositions, particularly those with smaller amounts of the inactive ingredients, would give absorption in humans equivalent to that of Sandimmune (registered trademark) or Neoral (registered trademark).
European Application No. 88305138.5 (publication No. 0294239) of Kurihara and Murano discloses solid compositions comprising a cyclosporin in admixture with an amount of alpha-cyclodextrin or a functional derivative thereof sufficient to solubilize the cyclosporin in water. However, the amount of alpha-cyclodextrin required is generally many times the amount of cyclosporin by weight, so that this approach appears incapable of providing dosage forms smaller than Sandimmune (registered trademark) or Neoral (registered trademark) capsules. Additionally, there is no indication that any of the disclosed compositions will, upon oral administration, give absorption equivalent to that of Sandimmune (registered trademark) or Neoral (registered trademark).
In Pharmaceutical Research, Vol. 8, No. 4, 1991, pp 518-522, Abdallah and Mayersohn disclose a tablet containing cyclosporine 100 mg, mannitol 250 mg, microcrystalline cellulose 200 mg, stearic acid 20 mg, and sodium dodecyl sulfate 10 mg. It is stated that the tablets gave absorption comparable to that of Sandimmune (registered trademark) in a comparative bioavailability study in dogs.
However, the relatively large amount of inactive ingredients used precludes tablets or capsules significantly smaller than Sandimmune (registered trademark) or Neoral (registered trademark), and there is no evidence given that such a formulation would give absorption equivalent to that of Sandimmune or Neoral in humans.
In view of the problems with prior art formulations, it is the object of the present invention to enable pharmaceutical compositions containing a cyclosporin (and in particular cyclosporine) with the following properties:
1. They are solid at room temperature and free of volatile solvents.
2. Upon oral administration, they enable absorption comparable to that of Sandimmune (registered trademark) or Neoral (registered trademark).
3. They enable capsules or tablets of smaller size than Sandimmune (registered trademark) and Neoral (registered trademark). That is to say, they enable compositions wherein the content of the cyclosporin by weight exceeds ten percent and preferably twenty percent of the weight of the composition.